cancer stem cell treatment strategy focusing on new atypical antipsychotics

• Project/Area Number: 17K15015
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Tumor therapeutics
• Research Institution: Yamagata University
• Principal Investigator: Suzuki Shuhei 山形大学, 医学部, 助教 (90637175)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2018: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000); Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: がん幹細胞 / ドラッグリポジショニング / 薬剤抵抗性 / ドパミン / セロトニン / 神経伝達物質 / ドラッグリポジショニグ / 抗精神病薬 / サバイビン / サイコオンコロジー / グリオブラストーマ / 肺がん / 膵がん / オランザピン / 癌幹細胞 / アリピプラゾール / 癌

Outline of Final Research Achievements

Our experiments cleared that newly-developed atypical antipsychotics (e.g., olanzapine and brexpiprazole) has anti-cancer and anti-cancer stem cell effects from the viewpoint of drug repositioning. These drugs enhance the anti-cancer effects of the widely-used cytotoxic agents like 5-FU and gemcitabine via reduction of survivin, a representative anti-apoptotic protein, not only in vitro but also in vivo. Moreover, our results revealed brexpiprazole gives an anti-cancer effect against glioblastoma stem-like cells to osimertinib, a less toxic third-generation epidermal growth factor receptor tyrosine kinase inhibitor, in vitro as well as in vivo. These findings have been published in medical journals in English and are already cited several times.

Academic Significance and Societal Importance of the Research Achievements

学術的意義：神経伝達物質や神経伝達物質受容体が、がんへどのような作用を示すかどうか検討していく中での嚆矢ともいえる知見を得ることができ、さらに詳細に、それらの働きや作用機序を詳らかにしていくことが可能となった。
社会的意義：ドラッグリポジショニングの視点から行われた研究であり、既に安全性が担保され、他疾患でではあるが保険承認の得られている薬剤を用いることから、身体的安全面や経済学的負担面から大きなメリットのある治療戦略といえて、実用へのハードルが非常に低いことが予測される。

Research Products

• [Journal Article] Brexpiprazole Reduces Survivin and Reverses EGFR Tyrosine Kinase Inhibitor Resistance in Lung and Pancreatic Cancer (2019)
  • Author(s): Tomomi Sanomachi, Shuhei Suzuki, Keita Togashi, Shizuka Seino, Takashi Yoshioka, Chifumi Kitanaka , Masashi Okada, Masahiro Yamamoto
  • Journal Title: Anticancer Res Volume: 9 Issue: 9 Pages: 4817-4828
  • DOI: 10.21873/anticanres.13667
  • Peer Reviewed
• [Journal Article] Brexpiprazole, a Serotonin-Dopamine Activity Modulator, Can Sensitize Glioma Stem Cells to Osimertinib, a Third-Generation EGFR-TKI, via Survivin Reduction (2019)
  • Author(s): Suzuki Shuhei、Yamamoto Masahiro、Sanomachi Tomomi、Togashi Keita、Sugai Asuka、Seino Shizuka、Yoshioka Takashi、Kitanaka Chifumi、Okada Masashi
  • Journal Title: Cancers Volume: 11 Issue: 7 Pages: 947-947
  • DOI: 10.3390/cancers11070947
  • Peer Reviewed / Open Access
• [Journal Article] In vitro and in vivo Anti-Tumor Effects of Brexpiprazole, a Newly-Developed Serotonin-Dopamine Activity Modulator With an Improved Safety Profile (2019)
  • Author(s): Shuhei Suzuki, Masahiro Yamamoto, Keita Togashi, Tomomi Sanomachi, Asuka Sugai, Shizuka Seino, Takashi Yoshioka, Chifumi Kitanaka, Masashi Okada
  • Journal Title: Oncotarget Volume: 37 Issue: 37 Pages: 3547-3558
  • DOI: 10.18632/oncotarget.26949
  • Peer Reviewed / Open Access
• [Journal Article] Involvement of GLUT1-mediated glucose transport and metabolism in gefitinib resistance of non-small-cell lung cancer cells. (2018)
  • Author(s): Suzuki S, Okada M, Takeda H, Kuramoto K, Sanomachi T, Togashi K, Seino S, Yamamoto M, Yoshioka T, Kitanaka C.
  • Journal Title: Oncotarget. Volume: 9 Issue: 66 Pages: 32667-32679
  • DOI: 10.18632/oncotarget.25994
  • Peer Reviewed / Open Access
• [Journal Article] Olanzapine, an Atypical Antipsychotic, Inhibits Survivin Expression and Sensitizes Cancer Cells to Chemotherapeutic Agents. (2017)
  • Author(s): Sanomachi T, Suzuki S, Kuramoto K, Takeda H, Sakaki H, Togashi K, Seino S, Yoshioka T, Okada M, Kitanaka C.
  • Journal Title: Anticancer Res. Volume: 37 Issue: 11 Pages: 6177-6188
  • DOI: 10.21873/anticanres.12067
  • Peer Reviewed
• [Presentation] 部分的ドパミン受容体アゴニストであるアリピプラゾールは癌幹細胞への抗腫瘍効果を示し、薬剤抵抗性を減弱させる (2018)
  • Author(s): 鈴木修平, 岡田雅司, 吉岡孝志, 北中千史.
  • Organizer: 第77回日本癌学会学術総会